Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereof

ABSTRACT

Optically active 2-hydroxytetrahydrothienopyridine derivatives represented by Formula I and pharmaceutically acceptable salts, preparation method and use in the manufacture of a medicament thereof are disclosed. The pharmacodynamic experiment results show that the present compounds of Formula I are useful for inhibiting platelet aggregation. The pharmacokinetic experiment results show that the present compound of Formula I can be converted in vivo into pharmacologically active metabolites and are therefore useful for inhibiting platelet aggregation. Therefore, the present compounds are useful for the manufacture of a medicament for preventing or treating thrombosis and embolism related diseases.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the priority of Chinese Patent Application No.201010104091.5, filed on Feb. 2, 2010 and entitled2-HYDROXYTHIENOPYRIDINE DERIVATIVES, PREPARATION METHOD AND MEDICAL USETHEREOF.

This application claims the priority of Chinese Patent Application No.201010624329.7, filed on Dec. 30, 2010, and entitled OPTICALLY ACTIVE2-HYDROXYTETRAHYDROTHIENOPYRIDINE DERIVATIVES, PREPARATION METHOD ANDUSE IN MANUFACTURE OF MEDICAMENT THEREOF.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the field of pharmacochemistry, andmore particularly to optically active 2-hydroxytetrahydrothienopyridinederivatives, preparation method and use thereof in the manufacture of amedicament, especially for preventing or treating thrombosis andembolism related diseases.

2. Description of the Related Art

Clopidogrel is an anti-platelet aggregation agent that is most widelyused all over the world at present, and used for treatingatherosclerosis, acute coronary syndrome (ACS), thromboticcomplications, and other diseases in clinic. Clinical tests in manyyears have demonstrated the efficacy and safety of clopidogrel forthrombotic cardio-cerebrovascular diseases (Lancet, 1996, 348: 1329).Clopidogrel is a precursor drug, which is metabolized in vivo throughtwo oxidative steps by the liver P450 enzyme system to generate anactive metabolite, which is covalently bound to P2Y₁₂ receptor on theplatelet surface to inhibit platelet aggregation through P2Y₁₂ receptorantagonism (Thromb Haemost, 2000, 84: 891). However, the researches onin-vivo metabolism of clopidogrel reveal that 85% of the prototype drugis hydrolyzed by human carboxylesterase 1 (hCE1) in the liver into aninactive carboxylic derivative of clopidogrel (J Pharmacol Exp Ther,2006, 319: 1467), which greatly reduces the oral bioavailability ofclopidogrel, resulting in the disadvantages of clopidogrel such as highdosage in clinical use (load dosage: 300 mg clopidogrel), slow onset ofaction, and delayed inhibition of platelets (Cardiovascular DrugReviews, 1993, 11: 180). In addition, due to the differential expressionof the P450 enzyme system in the liver among different individuals,clopidogrel that functions by metabolism by the P450 enzyme system hassignificant individual differences in clinical efficacy, including, forexample, the presence of “clopidogrel resistance”, and occurrence ofcardiovascular events including stent thrombosis (ST) (Circulation,2004, 109: 166).

Prasugrel, a new anti-platelet agent, is developed by SankyoPharmaceuticals Co., Ltd. and Eli Lilly Company. Compared withclopidogrel, prasugrel can more quickly and effectively inhibit plateletaggregation, but has a higher risk of bleeding. In elective percutaneouscoronary intervention (PCI) for treating acute coronary syndrome,compared with clopidogrel, prasugrel can significantly lower theincidence of ischemic events (including stent thrombosis), but thebleeding risk is increased (N Engl J Med, 2007, 357: 2001). Otheradverse effects of prasugrel include, for example, thrombocytopenia andneutropenia.

Certain 2-hydroxytetrahydrothienopyridine derivatives havinganti-platelet aggregation effect are disclosed in U.S. Pat. Nos.5,190,938, 5,874,581, and WO9749397. These compounds are, however,racemic mixtures, and to date, there have been no studies provingwhether their racemates and enantiomers are different in efficacy andsafety. In Chinese Patent Application No. 200810097756.7, certainaromatic heterocyclic carboxylate ester derivatives of prasugrel andclopidogrel, especially certain racemic derivatives of prasugrel, aredisclosed, but optically active alkyl carboxylate derivatives and otherrelated derivatives of 2-hydroxytetrahydrothienopyridine are notinvolved.

Therefore, there is a need in clinic for development of a newanti-platelet aggregation agent that has a rapid onset of action andhigh efficacy, and can avoid the bleeding side effect.

SUMMARY OF THE INVENTION

Therefore, in order to overcome the above disadvantages, an objective ofthe present invention is to design and synthesize new ester derivativesof 2-hydroxytetrahydrothienopyridine, so as to develop anti-plateletaggregation agents that have good efficacy and low side effects.

The present invention discloses an optically active2-hydroxytetrahydrothienopyridine derivative, for example, a compound ofgeneral Formula I, or a pharmaceutically acceptable salt or hydratethereof:

where R¹ is a non-substituted or X-substituted linear or branched C₁₋₁₀alkyl, OR⁴, NR⁵R⁶, phenyl, a Y-substituted phenyl, styryl,4-hydroxystyryl, 4-hydroxy-3-methoxystyryl, 3-pyridinyl, alkenyl, oralkynyl, in which X is fluoro, chloro, bromo, iodo, cyano, nitro, amino,amido, sulfonamido, trifluoromethyl, mercapto, hydroxyl, acetoxy,methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, aryloxy,phenyl or a Y-substituted phenyl; Y is fluoro, chloro, bromo, iodo,cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto,hydroxy, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl orethoxycarbonyl, and the Y group is at position 2, 3 or 4 of the phenylring;

R² is H, fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido,sulfonamido, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy,ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, a linear or branchedC₁₋₆ alkyl, alkenyl or alkynyl, and is at position 2, 3 or 4 of thephenyl ring; and when R² is 2-chloro, R¹ is not phenyl, and when R² is2-halo, R¹ is not 3-pyridinyl;

R³ is a linear or branched C₁₋₆ alkyl or a C₁₋₆ cycloalkyl;

R⁴ is a linear or branched C₁₋₁₀ alkyl, or benzyl; and R⁵ and R⁶ eachare a linear or branched C₁₋₆ alkyl, or NR⁵R⁶ is

In the present compound of Formula I, R¹ is preferably a non-substitutedor X-substituted linear or branched C₁₋₆ alkyl, OR⁴, NR⁵R⁶, phenyl, aY-substituted phenyl, styryl, 4-hydroxylstyryl,4-hydroxy-3-methoxystyryl, or 3-pyridinyl, in which X is amino, amido,sulfonamido, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl,methoxycarbonyl, ethoxycarbonyl, aryloxy, phenyl, or a Y-substitutedphenyl; Y is fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido,sulfonamido, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl,methoxycarbonyl, or ethoxycarbonyl, and is at position 2, 3 or 4 of thephenyl ring; R⁴ is a linear or branched C₁₋₆ alkyl, or benzyl; and R⁵and R⁶ is a linear or branched C₁₋₆ alkyl, or NR⁵R⁶ is

In the present compound of Formula I, R¹ is more preferably methyl,ethyl, propyl, t-butyl, tert-pentyl, phenoxymethyl, methoxy, ethoxy,isopropoxy, isobutoxy, benzyloxy, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₃)(CH₂CH₃),

phenyl, 2-hydroxyphenyl, 2-acetoxyphenyl, 4-methoxyphenyl,4-nitrophenyl, styryl, 4-hydroxylstyryl, 4-hydroxy-3-methoxystyryl, or3-pyridinyl.

In the present compound of Formula I, R² is preferably 2-fluoro,2-chloro, 2-bromo, 2-cyano, or 2-trifluoromethyl, and when R² is2-chloro, R¹ is not phenyl, and when R² is 2-halo, R¹ is not3-pyridinyl.

In the present compound of Formula I, R² is preferably 2-fluoro or2-chloro.

In the present compound of Formula I, R³ is more preferably methyl orethyl.

Preferred compounds of the present invention are:

-   (S)-methyl    2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-2;-   (S)-methyl    2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chloro    phenyl)-acetate I-3;-   (S)-methyl    2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-4;-   (S)-methyl    2-(2-(2-acetoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-5;-   (S)-methyl    2-(2-pivaloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-7;-   (S)-methyl    2-(2-(2,2-dimethylbutanoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-8;-   (S)-methyl    2-(2-cinnamoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-9;-   (S)-methyl    2-(2-(4-methoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-11;-   (S)-methyl    2-(2-phenylacetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-12;-   (S)-methyl    2-(2-(phenoxyacetoxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-13;-   (S)-methyl    2-(2-(ethoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-14;-   (S)-methyl    2-(2-(isobutoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-15;-   (S)-methyl    2-(2-(isopropoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-16;-   (S)-methyl    2-(2-(benzyloxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-17;-   (S)-methyl    2-(2-(N,N-dimethylcarbamoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-18;-   (S)-methyl    2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate    I-19;-   (S)-methyl    2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(4-chlorophenyl)-acetate    I-20;-   (S)-methyl    2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-phenyl-acetate    I-21;-   (S)-methyl    2-(2-(pyrrolicline-1-carbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-22;-   (S)-methyl    2-(2-(methoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-23;-   (S)-methyl    2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromophenyl)-acetate    I-24;-   (S)-ethyl    2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate    I-25;-   (S)-ethyl    2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-26;-   (S)-ethyl    2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromopheny    1)-acetate I-27;-   (S)-methyl    2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluoro    phenyl)-acetate I-28;-   (S)-methyl    2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromo    phenyl)-acetate I-29;-   (S)-ethyl    2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluoro    phenyl)-acetate I-30;-   (S)-ethyl    2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-31;-   (S)-ethyl    2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromo    phenyl)-acetate I-32;-   (S)-methyl    2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate    I-33;-   (S)-methyl    2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromophenyl)-acetate    I-34;-   (S)-ethyl    2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate    I-35;-   (S)-ethyl    2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-36;-   (S)-ethyl    2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromophenyl)-acetate    I-37;-   (S)-ethyl    2-(2-pivaloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-38;-   (S)-ethyl    2-(2-(2,2-dimethylbutanoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-39;-   (S)-methyl    2-(2-feruloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-40;-   (S)-methyl    2-(2-benzoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate    I-41;-   (S)-methyl    2-(2-nicotinoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(4-chlorophenyl)-acetate    I-42;-   (S)-methyl    2-(2-(2-hydroxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-43;-   (S)-methyl    2-(2-(t-butoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-44;-   (S)-methyl    2-(2-(N,N-diethylcarbamoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-45; and-   (S)-methyl    2-(2-(piperidine-1-carbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate    I-46.

The present compound of Formula I has an optical purity of 70-100%,preferably 90-100%, more preferably 95-100%, and most preferably98-100%.

The derivative of the present invention also includes an enantiomer anda racemate of the compound of Formula I.

The derivative of the present invention also includes a pharmaceuticallyacceptable salt of the compound of Formula I, including, but not limitedto, an acid addition salt formed by the compound of the presentinvention with an acid below: hydrochloric acid, hydrobromic acid,sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid,acetic acid, maleic acid, fumaric acid, malic acid, mandelic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,pamoic acid, oxalic acid, or succinic acid.

Another objective of the present invention is to provide a method forpreparing an optically active 2-hydroxytetrahydrothienopyridinederivative represented by Formula I, as shown in reaction schemes below.

In the above reaction scheme, R¹, R², and R³ are as defined above in thecompound of Formula I; and R⁷ is a C₁₋₆ alkyl, trifluoromethyl,pentafluoroethyl, heptafluoropropyl, phenyl, or a Z-substituted phenyl,in which Z is a C₁₋₃ alkyl, halo, cyano, nitro, or trifluoromethyl, andis at position 2, 3 or 4 of the phenyl ring.

The method specifically comprises the following steps:

(1) A compound of Formula II ((R)-2-(R⁷-sulfonyloxy)-2-(R² substitutedphenyl)acetate) is reacted with a compound of Formula III(5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one) or a salt thereof(at a molar ratio of 1:2-2:1) in the presence of a base (in an amount of1-10 eq of the compound of Formula II), to obtain a compound of FormulaIV ((2S)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-2-(R²substituted phenyl)acetate) or a salt thereof, where the solvent used isone or more selected from benzene, toluene, chloroform, n-hexane,cyclohexane, dichloromethane, 1,2-dichloroethane, methyl t-butyl ether,carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate,methanol, ethanol, acetone, tetrahydrofuran, diethyl ether,acetonitrile, N,N-dimethyl formamide, or dimethyl sulfoxide, andpreferably N,N-dimethyl formamide, tetrahydrofuran, acetonitrile, ordichloromethane; the base used may be triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, potassium carbonate,sodium carbonate, potassium bicarbonate, or sodium bicarbonate; thereaction temperature is from −20° C. to 100° C., and preferably from 10°C. to 60° C.; and the salt of the compound of Formula III is selectedfrom hydrochloride, p-toluenesulfonate, acetate, sulfate, phosphate,trifluoromethanesulfonate, oxalate, methanesulfonate, benzenesulfonate,or hydrobromide; and

(2) The compound of Formula IV or the salt thereof is reacted with acompound of Formula V (an anhydride) or a compound of Formula VI(R¹-carbonyl chloride) (at a molar ratio of 1:1-1:10) in the presence ofa base (in an amount of 1-10 eq of the compound of Formula IV), toobtain the compound of Formula I((S)-2-(2-R¹-carbonyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(R²substituted phenyl)-acetate); where the reaction solvent used is one ormore selected from benzene, toluene, chloroform, n-hexane, cyclohexane,dichloromethane, 1,2-dichloroethane, methyl t-butyl ether, carbontetrachloride, ethyl acetate, propyl acetate, butyl acetate, methanol,ethanol, acetone, tetrahydrofuran, diethyl ether, acetonitrile,N,N-dimethyl formamide, or dimethyl sulfoxide, and preferablytetrahydrofuran, acetonitrile, or N,N-dimethyl formamide; the base usedis selected from triethylamine, sodium hydride, potassium hydride,1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, diisopropylethylamine,lithium diisopropylamide, potassium carbonate, sodium carbonate,potassium bicarbonate, sodium bicarbonate, potassium t-butoxide, orsodium t-butoxide; and the reaction temperature is from −20° C. to 100°C., and preferably from 0° C. to 50° C.

In the reaction scheme, R¹, R², R³, and R⁷ are as defined above in thecompounds of Formulae I and II.

The method specifically comprises the following step:

the compound of Formula II is reacted with a compound of Formula VII(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl carboxylate) or a saltthereof in the presence of a base, to obtain the compound of Formula I;where the solvent used is one or more selected from benzene, toluene,chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane,methyl t-butyl ether, carbon tetrachloride, ethyl acetate, propylacetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran,diethyl ether, acetonitrile, N,N-dimethyl formamide, or dimethylsulfoxide, and preferably N,N-dimethyl formamide, tetrahydrofuran,acetonitrile, or dichloromethane; the base used is selected fromtriethylamine, diisopropyl ethylamine,1,8-diazabicyclo[5,4,0]undec-7-ene, potassium carbonate, sodiumcarbonate, potassium bicarbonate, or sodium bicarbonate; the reactiontemperature is from −20° C. to 100° C., and preferably 10° C. to 60° C.;and the salt of the compound of Formula VII is selected fromhydrochloride, p-toluenesulfonate, acetate, sulfate, phosphate,trifluoromethanesulfonate, oxalate, methanesulfonate, benzenesulfonate,or hydrobromide.

The compound of Formula VII or the salt thereof may be preparedfollowing the method described in U.S. Pat. No. 5,190,938.

The enantiomer of the present compound of general Formula I may beprepared following Methods (I) and (2) above, except that an enantiomerof the compound of Formula II is used as a starting material.

The racemate of the present compound of general Formula I may beprepared following Methods (I) and (2) above, except that a racemate ofthe compound of Formula II is used as a starting material.

A further objective of the present invention is to provide a use of anoptically active 2-hydroxytetrahydrothienopyridine derivativerepresented by Formula I in the preparation of a medicament.

Pharmacodynamic experiment results show that the present compounds ofgeneral Formula I have significant inhibition effect of plateletaggregation, and the anti-platelet aggregation effect of some compoundsis obviously superior to that of clopidogrel. In addition, the compoundof Formula I (S configuration) generally exhibits a more potent plateletaggregation inhibition than the corresponding enantiomer (Rconfiguration) and racemic mixture thereof. Pharmacokinetic experimentresults show that the present compound of Formula I can be effectivelyconverted in vivo into a pharmacologically active metabolite, so as toexert the platelet aggregation inhibition, and the bioavailability of anintermediate metabolite from which the active metabolite is formed isobviously higher than that of clopidogrel. The above experiment resultssuggest that the compound of the present invention or a pharmaceuticallyacceptable salt thereof is useful in the preparation of a medicament forpreventing or treating thrombosis and embolism related diseases,especially atherosclerosis, myocardial infarction, stroke, ischemiccerebral thrombosis, peripheral arterial disease, acute coronarysyndrome, or thrombosis after percutaneous coronary intervention (PCI).

The present invention also provides a pharmaceutical composition forpreventing or treating thrombosis and embolism related diseases,comprising a therapeutically effective amount of the compound of FormulaI or a pharmaceutically acceptable salt thereof as an active ingredient,and a pharmaceutically acceptable carrier. The pharmaceuticalcomposition may be in any of conventional pharmaceutical dosage formssuch as ordinary tablets or capsules, sustained release tablets orcapsules, controlled release tablets or capsules, granules, powders,syrups, oral solutions, and injections.

The dosage of the compound of Formula I in the pharmaceuticalcomposition of the present invention varies depending on factors such asthe symptoms and age. For an adult, it is orally administered per doseat a lower limit of 0.1 mg (preferably 1 mg) and an upper limit of 1000mg (preferably 500 mg), or is intravenously administrated per dose at alower limit of 0.01 mg (preferably 0.1 mg) and an upper limit of 500 mg(preferably 250 mg). The dosage may fall outside the above rangesaccording to the severity of the disease and the dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows ¹H NMR spectra of Compound I-2.

FIG. 2 shows chiral HPLC analysis of Compound I-2.

FIG. 3 shows chiral HPLC analysis of Compound I-2′ (an enantiomer ofI-2).

FIG. 4 shows chiral HPLC analysis of Compound I-2″ (a racemic mixture ofI-2).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The contents of the present invention will be described in detail bymeans of examples. The examples are provided herein for illustrativepurposes only, and are not intended to limit the scope of the presentinvention.

Example 1 (R)-Methyl o-chloromandelate

(R)-o-chloromandelic acid (5.6 g) was dissolved in 23.1 ml of methanol,and then a catalytic amount of concentrated sulfuric acid (0.12 ml) wasadded, and heated to reflux for 2 hrs. After cooling, methanol wasevaporated under reduced pressure, and the residue was dissolved indichloromethane, and washed sequentially with 10% aqueous potassiumcarbonate solution and water. The dichloromethane solution was dried,and evaporated to dryness, to give 5.79 g of (R)-methylo-chloromandelate as a clear colorless oil. Yield 96%. ¹H-NMR (300 MHz,CDCl₃) δ 3.52 (d, 1H, J=4.8 Hz), 3.78 (s, 3H), 5.57 (d, 1H, J=4.5 Hz),7.26-7.31 (m, 2H), 7.37-7.41 (m, 2H); ESI-MS m/z 222.9 [M+Na]⁺.

Example 2 (R)-Methyl2-(2-chlorophenyl)-2-(4-nitrophenylsulfonyloxy)-acetate (II-1)

(R)-Methyl o-chloromandelate (98.4 g, 0.49 mol, ee=99%) was dissolved in500 ml of anhydrous dichloromethane, and then 91 ml of triethylamine(0.65 mol) and a catalytic amount of DMAP were added. 120 g (0.54 mol)of p-nitrophenylsulfonyl chloride was dissolved in 500 ml of anhydrousdichloromethane, which was added dropwise into the reaction solution at0° C., and reacted for 4-5 hrs at 0° C. Water (500 ml) was added to thereaction solution and the layers were separated. The aqueous phase wasextracted with dichloromethane (150 ml×3), and the organic phases werecombined and dried, and dichloromethane was evaporated under reducedpressure to afford 206.5 g of a crude product as a dark red oil, whichwas recrystallized in methanol to obtain 154.5 g of a solid product(II-1). Yield 82%. ¹H-NMR (300 MHz, CDCl₃) δ 3.57 (s, 3H), 6.39 (s, 1H),7.21-7.39 (m, 4H), 8.07 (d, 2H, J=8.9 Hz), 8.30 (d, 2H, J=8.9 Hz);ESI-MS ink 408.0 [M+Na]⁺.

Example 3 (2S)-Methyl2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-2-(2-chlorophenyl)-acetate(IV-1)

58.1 g (0.15 mol) of (R)-methyl2-(2-chlorophenyl)-2-(4-nitrophenylsulfonyloxy)-acetate (II-1), 32.3 g(0.17 mol) of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-onehydrochloride (III-1), and 37.8 g (0.38 mol) of potassium bicarbonatewere added to 500 ml of acetonitrile. The reaction was stirred under anitrogen atmosphere at room temperature for 26 hrs. The reactionsolution was allowed to stand and the insoluble material was filteredoff, to obtain a dark red mother liquor. The solvent was evaporatedunder reduced pressure, and 35.4 g of an oil product was obtained afterpurification by flash column chromatography (petroleum ether:ethylacetate=4:1). Yield 70%. Recrystalization from ethanol afforded 18.1 gof a pure product (IV-1) as a white solid. mp: 146-148° C., ee=97.5%,[α]_(D) ¹⁹=+114.0° (c 0.5, MeOH); ¹H-NMR (300 MHz, CDCl₃) δ 1.79-1.93(m, 1H), 2.30-2.40 (m, 1H), 2.56-2.70 (m, 1H), 3.00-3.27 (m, 2H), 3.72(s, 3H), 3.79-3.93 (m, 1H), 4.12-4.19 (m, 1H), 4.89 (d, 1H, J=5.6 Hz),6.00 (d, 1H, J=5.2 Hz), 7.26-7.50 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ33.9, 34.0, 49.0, 49.7, 51.1, 51.6, 52.2, 52.4, 67.3, 76.6, 77.0, 77.4,126.6, 126.8, 127.2, 129.8, 130.1, 132.7, 134.8, 167.2, 167.4, 170.8,198.6; ESI-MS m/z 338.1 [M+H]⁺; HRMS Calcd for C₁₆H₁₇NO₃SCl [M+H]⁺ m/z338.0618, found 338.0626.

Example 4 (S)-Methyl2-(2-benzoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-1)

(2S)-Methyl2-(2-chlorophenyl)-2-(2-oxo-5,6,7,7a-tetrahydrothieno[3,2-c]pyridinyl)acetate(IV-1) (113 mg) was dissolved in acetonitrile (10 ml), 0.10 ml oftriethylamine was added, and 151 mg of benzoic anhydride was addeddropwise at 0° C., and then the mixture was warmed to room temperatureand reacted for 2 hrs. The reaction solution was poured into water (30ml), the aqueous phase was extracted with ethyl acetate (50 ml×3), andthe organic phase was washed with saturated aqueous sodium bicarbonatesolution and saturated saline, dried over anhydrous sodium sulfate, andevaporated, to obtain a crude product, which was subjected to flashcolumn chromatography (petroleum ether:ethyl acetate=40:3), to obtain(S)-methyl2-(2-benzoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-1) (77 mg). Yield 52%, mp: 84-86° C., ee=93.5% (chiral HPLC analysisconditions: Chiralpak IC 4.6 mm×250 mm; column temperature: 25° C.;mobile phase: 90% n-hexane/10% isopropanol/0.1% diethylamine; flow rate:0.5 ml/min; and detection wavelength: UV 254 nm), [α]_(D) ²⁰=+34.00° (c0.50, MeOH); ¹H-NMR (300 MHz, CDCl₃) δ 2.82-2.93 (m, 4H), 3.57-3.68 (m,2H), 3.73 (s, 3H), 4.95 (s, 1H), 6.42 (s, 1H), 7.26-8.17 (m, 9H);¹³C-NMR (75 MHz CDCl₃) δ 25.0, 48.2, 50.4, 52.2, 67.8, 112.1, 125.9,127.2, 128.5, 128.6, 129.5, 129.8, 130.0, 130.2, 133.9, 134.7, 149.9,163.5; ESI-MS m/z 442.1 [M+H]⁺; HRMS Calcd for C₂₃H₂₁NO₄SCl [M+H]⁺ m/z442.0891, found 442.0880.

Example 5 (S)-Methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-2)

Following the method described in Example 4, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-5, 6, 7,7a-tetrahydrothieno[3,2-c]pyridinyl)acetate (IV-1) (6.5 g) was reactedwith acetic anhydride (3.6 ml), to prepare (S)-methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-2) (6.8 g). Yield 93%. Recrystallization from ethanol afforded awhite solid, mp: 73-75° C., ee=98.9% (chiral HPLC analysis conditions:Chiralpak IC 4.6 mm×250 mm; column temperature: 25° C.; mobile phase:92% n-hexane/8% tetrahydrofuran/0.1% diethylamine; flow rate: 0.5ml/min; and detection wavelength: UV 254 nm), [α]_(D) ²³=+45.00° (c=1.0,CH₃OH); ¹H-NMR (300 MHz, CDCl₃) δ 2.26 (s, 3H), 2.65-2.90 (m, 4H),3.47-3.69 (m, 2H), 3.72 (s, 3H), 4.92 (s, 1H), 6.26 (s, 1H), 7.24-7.70(m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 20.2, 24.5, 47.6, 49.8, 51.6, 67.3,111.5, 125.3, 126.6, 128.8, 128.9, 129.3, 129.4, 133.3, 134.2, 149.1,167.2, 170.7; ESI-MS m/z 380.0 [M+H]⁺; HRMS Calcd for C₁₈H₁₉NO₄SCl[M+H]⁺ m/z 380.0723, found 380.0737.

Example 6 (R)-Methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl-acetate(I-2′)

Following the method described in Example 4, (2R)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1′) (prepared following Examples I-3) was reacted with aceticanhydride, to prep are (R)-methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-2′), ee=98.2% (chiral HPLC analysis conditions were the same as thosein Example 5), [α]_(D) ²³=−44.00° (c=1.0, CH₃OH).

Example 7 (S)-Methyl2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-3)

Following the method described in Example 4, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) (338 mg) was reacted with propionic anhydride (0.27 ml), toprepare (S)-methyl2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-3) (267 mg). Yield 66%, ee=96.5% (chiral HPLC analysis conditionswere the same as those in Example 4), [α]_(D) ²⁰=+36.00° (c 0.50, MeOH);¹H-NMR (300 MHz, CDCl₃) δ 1.23 (t, 3H, J=7.4 Hz), 2.55 (q, 2H, J=7.7Hz), 2.76-2.78 (m, 2H), 2.87-2.88 (m, 2H), 3.53 (d, 1H, J=14.2 Hz), 3.65(d, 1H, J=13.6 Hz), 3.72 (s, 3H), 4.91 (s, 1H), 6.26 (s, 1H), 7.26-7.69(m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 8.8, 21.1, 25.0, 27.4, 48.2, 50.3,52.2, 67.8, 106.2, 111.7, 125.6, 127.2, 129.1, 129.5, 129.8, 130.0,123.7, 149.8, 171.2; ESI-MS m/z 394.1 [M+H]⁺; HRMS Calcd forC₁₉H₂₁NO₄SCl [M+H]⁺ m/z 394.0883, found 394.0880.

Example 8 (S)-methyl2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-4)

Following the method described in Example 4, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) (86 mg) was reacted with butyric anhydride (90 μl), to prepare(S)-methyl2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H-yl)-2-(2-chlorophenyl)-acetate(I-4) (51 mg). Yield 49%, ee 96.3% (chiral HPLC analysis conditions werethe same as those in Example 4), [α]_(D) ²⁰=+32.00° (c 0.50, MeOH);¹H-NMR (300 MHz, CDCl₃) δ 1.00 (t, 3H, J=5.2 Hz), 1.74 (q, 2H, J=5.2Hz), 2.47-2.52 (m, 2H), 2.76-2.78 (m, 2H), 2.86-2.89 (m, 2H), 3.53 (d,1H, J=14.3 Hz), 3.65 (d, 1H, J=14.2 Hz), 3.72 (s, 3H), 4.90 (s, 1H),6.25 (s, 1H), 7.24-7.69 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 13.5, 18.2,25.0, 35.8, 48.2, 50.3, 52.1, 67.9, 111.8, 125.7, 127.1, 129.2, 129.4,129.8, 130.0, 133.8, 134.7, 149.7, 170.4, 171.2; ESI-MS m/z 408.1[M+H]⁺; HRMS Calcd for C₂₀H₂₃NO₄SCl [M+H]⁺ m/z 408.1035, found 408.1036.

Example 9 (S)-methyl2-(2-(2-acetoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-5)

338 mg of (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) was dissolved in 15 ml of tetrahydrofuran, 0.83 ml oftriethylamine was added dropwise and stirred for 10 minutes, and then600 mg of acetylsalicylic chloride was added and stirred at roomtemperature for 24 hrs. The reaction solution was poured into saturatedaqueous NaHCO₃ solution (20 ml), extracted with ethyl acetate (50 ml×3),concentrated, evaporated, and subjected to flash column chromatography(petroleum ether:ethyl acetate=5:1), to obtain (S)-methyl2-(2-(2-acetoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-5) (280 mg). Yield: 56%, ee=96.1% (chiral HPLC analysis conditions:Chiralpak IC 4.6 mm×250 mm; column temperature: 25° C.; mobile phase:85% n-hexane/15% tetrahydrofuran/0.1% diethylamine; flow rate: 0.5ml/min; and detection wavelength: UV 254 nm), [α]_(D) ²⁰=+14.00° (c0.50, CHCl₃); ¹H-NMR (300 MHz, CDCl₃) δ 2.34 (s, 3H), 2.79-2.81 (m, 2H),2.90-2.93 (m, 2H), 3.54-3.66 (m, 2H), 3.72 (s, 3H), 4.93 (s, 1H), 6.37(s, 1H), 7.14-7.36 (m, 4H), 7.39-8.15 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ20.93, 24.93, 48.04, 50.12, 52.12, 67.65, 112.61, 117.34, 118.97,121.66, 124.09, 126.14, 127.12, 129.35, 129.45, 129.79, 129.92, 130.71,132.12, 133.54, 134.71, 135.73, 149.32, 151.12, 161.32, 169.47, 171.17;ESI-MS m/z 500 [M+H]⁺, 522 [M+Na]⁺; HRMS Calcd for C₂₅H₂₃NO₆SCl [M+H]⁺m/z 500.0931, found 500.0935.

Example 10 (S)-methyl2-(2-nicotinoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-6)

Following the method described in Example 9, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) (338 mg) was reacted with nicotinoyl chloride (512 mg), toprepare (S)-methyl2-(2-nicotinoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-6) (173 mg). Yield: 39%, mp: 92-94° C., ee=97.7% (chiral HPLCanalysis conditions: Chiralpak IC 4.6 mm×250 mm; column temperature: 25°C.; mobile phase: 50% n-hexane/50% isopropanol/0.1% diethylamine; flowrate: 0.8 ml/min; and detection wavelength: UV 254 nm), [α]_(D)²⁰=+34.00° (c 0.50, MeOH); ¹H-NMR (500 MHz, CDCl₃) δ 2.80-2.82 (m, 2H),2.91-2.93 (m, 2H), 3.58 (d, 1H, J=14.3 Hz), 3.69 (d, 1H, J=14.3 Hz),3.71 (s, 3H), 4.93 (s, 1H), 6.45 (s, 1H), 7.25-7.45 (m, 4H), 7.69 (m,1H), 8.38-8.41 (m, 1H), 8.83-8.84 (m, 1H), 9.34 (m, 1H); ¹³C-NMR (75MHz, CDCl₃) δ 24.93, 48.05, 50.24, 52.11, 67.73, 112.43, 123.47, 124.66,126.33, 127.11, 129.32, 129.43, 129.78, 129.89, 133.59, 134.68, 137.54,149.18, 151.19, 154.07, 162.17, 171.16; ESI-MS m/z 443.1 [M+H]⁺, 465.1[M+Na]⁺; HRMS Calcd for C₂₂H₂₀N₂O₄SCl [M+H]⁺ m/z 443.0839, found443.0832.

Example 11 (S)-methyl2-(2-pivaloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-7)

Preparation Method (1)

Following the method described in Example 9, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-cpyridin-5(2H,4H,6H)-yl)-acetate (IV-1) (338 mg) was reacted withpivaloyl chloride (738 μl), to prepare (S)-methyl2-(2-pivaloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-7) (360 mg). Yield: 85%, mp: 105-107° C., ee=99.1% (chiral HPLCanalysis conditions were the same as those in Example 5), [α]_(D)²⁰=+38.00. (c 0.50, MeOH); ¹H-NMR (300 MHz, CDCl₃) δ 1.30 (s, 9H),2.77-2.79 (m, 2H), 2.87-2.88 (m, 2H), 3.53 (d, 1H, J=14.2 Hz), 3.65 (d,1H, J=14.2 Hz), 3.72 (s, 3H), 4.90 (s, 1H), 6.26 (s, 1H), 7.23-7.69 (m,4H); ¹³C-NMR (75 MHz, CDCl₃) δ 24.93, 26.95, 39.09, 48.12, 50.29, 52.09,67.77, 111.39, 125.53, 127.10, 129.01, 129.38, 129.76, 129.92, 133.73,134.68, 150.08, 171.20, 175.17; ESI-MS m/z 422.2 [M+H]⁺; HRMS Calcd forC₂₁H₂₅NO₄SCl [M+H]⁺ m/z 422.1198, found 422.1193.

Preparation Method (2)

58.1 mg (0.15 mmol) of (R)-methyl2-(2-chlorophenyl)-2-(4-nitrophenylsulfonyloxy)-acetate (II-1), 47 mg(0.17 mmol) of 4,5,6,7-tetrahydrothieno[3.2-c]pyridin-2-yl pivalatehydrochloride (VII-1) (prepared following the method described in U.S.Pat. No. 5,190,938) and 38 mg (0.38 mmol) of potassium bicarbonate wereadded to 5 ml of acetonitrile. The reaction was stirred under a nitrogenatmosphere at room temperature overnight. After the reaction solutionwas allowed to stand, the insoluble material was filtered off, and thesolvent was evaporated under reduced pressure. After flash columnchromatography (petroleum ether:ethyl acetate=4:1), (S)-methyl2-(2-pivaloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H-yl)-2-(2-chlorophenyl)-acetate(I-7) (43 mg) was obtained. Yield 69%.

Example 12 (S)-Methyl2-(2-(2,2-dimethylbutanoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-8)

Following the method described in Example 9, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate (IV-1) (338 mg)was reacted with 2,2-dimethylbutanoyl chloride (824 μl), to prepare(S)-methyl2-(2-(2,2-dimethylbutanoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-8) (326 mg). Yield: 75%, mp: 98-100° C., ee=99.5% (chiral HPLCanalysis conditions were the same as those in Example 5), [α]_(D)²⁰=+36.00° (c 0.50, MeOH); ¹H-NMR (300 MHz, CDCl₃) δ 0.88 (t, 3H, J=7.4Hz), 1.26 (s, 6H), 1.64 (q, 2H, J=7.3 Hz), 2.76-2.78 (m, 2H), 2.87-2.88(m, 2H), 3.53 (d, 1H, J=14.3 Hz), 3.65 (d, 1H, J=14.3 Hz), 3.71 (s, 3H),4.90 (s, 1H), 6.25 (s, 1H), 7.22-7.69 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ9.2, 24.47, 24.99, 33.32, 43.11, 48.16, 50.31, 52.11, 67.82, 111.49,125.59, 127.11, 129.10, 129.40, 129.78, 129.95, 133.78, 134.70, 150.03,171.24, 174.73; ESI-MS m/z 436.2 [M+H]⁺; HRMS Calcd for C₂₂H₂₇NO₄SCl[M+H]⁺, m/z 436.1352, found 436.1349.

Example 13 (S)-methyl2-(2-cinnamoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-9)

Following the method described in Example 9, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate (IV-1) (338 mg)was reacted with cinnamoyl chloride (1.0 g), to prepare (S)-methyl2-(2-cinnamoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-9) (162 mg). Yield: 35%, mp: 122-124° C., ee=98.7%(chiral HPLC analysis conditions: Chiralpak IC 4.6 mm×250 mm; columntemperature: 25° C.; mobile phase: 90% n-hexane/10% tetrahydrofuran/0.1%diethylamine; flow rate: 0.5 ml/min; and detection wavelength: UV 254nm), [α]_(D) ²⁰=+14.00° (c 0.50, CHCl₃); ¹H-NMR (300 MHz, CDCl₃) δ2.79-2.81 (m, 2H), 2.89-2.90 (m, 2H), 3.51 (d, 1H, J=18.3 Hz), 3.63 (d,1H, J=20.3 Hz), 3.72 (s, 3H), 4.92 (s, 1H), 6.35 (s, 1H), 6.56 (d, 1H,J=15.9 Hz), 7.24-7.32 (m, 2H), 7.39-7.42 (m, 4H), 7.55-7.58 (m, 2H),7.69-7.71 (m, 1H), 7.85 (d, 1H, J=15.9 Hz); ¹³C-NMR (75 MHz, CDCl₃) δ25.01, 48.17, 50.36, 52.15, 67.83, 111.78, 116.04, 125.84, 127.15,128.36, 128.66, 128.99, 129.44, 129.81, 130.90, 133.98, 134.72, 147.39,163.69, 171.20; ESI-MS m/z 468.2 [M+H]⁺, 490.2 [M+Na]⁺; HRMS Calcd forC₂₅H₂₃NO₄SCl [M+H]⁺ m/z 468.1032, found 468.1036.

Example 14 (S)-methyl2-(2-(4-nitrobenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-10)

Following the method described in Example 9, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridine-5(2H,4H,6H)-yl)-acetate (IV-1) (338 mg)was reacted with p-nitrobenzoyl chloride (1.13 g), to prepare (S)-methyl2-(2-(4-nitrobenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-10) (125 mg). Yield: 26%, mp: 100-102° C., ee=100% (chiral HPLCanalysis conditions: Chiralpak IC 4.6 mm×250 mm; column temperature: 25°C.; mobile phase: 50% n-hexane/50% isopropanol/0.1% diethylamine; flowrate: 0.5 ml/min; and detection wavelength: UV 254 nm), [α]_(D)²⁰=+30.00° (c 0.50, MeOH); ¹H-NMR (300 MHz, CDCl₃) δ 2.82-2.84 (m, 2H),2.91-2.95 (m, 2H), 3.59 (d, 1H, J=14.3 Hz), 3.69 (d, 1H, J=14.3 Hz),3.73 (s, 3H), 4.95 (s, 1H), 6.47 (s, 1H), 7.26-7.70 (m, 4H), 8.18 (s,4H); ¹³C-NMR (75 MHz, CDCl₃) δ 25.14, 29.76, 48.17, 49.76, 50.38, 51.15,51.69, 52.28, 67.37, 67.86, 112.66, 123.86, 126.68, 127.26, 129.53,129.85, 130.00, 131.39, 133.69, 133.98, 134.84, 149.27, 151.08, 161.75,171.35; ESI-MS m/z 487.0 [M+H]⁺; HRMS Calcd for C₂₃H₂₀N₂O₆SCl [M+H]⁺ m/z487.0736, found 487.0731.

Example 15 (S)-Methyl2-(2-(4-methoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-11)

Following the method described in Example 9, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)acetate(IV-1) (338 mg) was reacted with p-methoxybenzoyl chloride (1.02 g), toprepare (S)-methyl2-(2-(4-methoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-11) (142 mg). Yield: 30%, ee=96.9% (chiral HPLC analysis conditionswere the same as those in Example 14), [α]_(D) ²⁰=+26.00° (c 0.50,MeOH); ¹H-NMR (300 MHz, CDCl₃) δ 2.79-2.90 (m, 4 H), 3.59-3.66 (m, 2H),3.71 (s, 3H), 3.85 (s, 3H), 4.92 (s, 1H), 6.38 (s, 1H), 6.92-6.95 (m,2H), 7.26-7.68 (m, 4H), 8.06-8.09 (m, 2H); ¹³C-NMR (75 MHz, CDCl₃) δ25.05, 48.15, 50.36, 52.09, 55.49, 67.85, 111.86, 113.62, 114.14,120.66, 121.24, 125.79, 127.13, 129.43, 129.79, 129.95, 132.31, 132.77,133.78, 134.69, 149.95, 163.17, 164.58, 171.22; ESI-MS m/z 472.2 [M+H]⁺,494.2 [M+Na]⁺; HRMS Calcd for C₂₄H₂₃NO₅SCl [M+H]⁺ m/z 472.0993, found472.0985.

Example 16 (S)-Methyl2-(2-phenylacetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-12)

Following the method described in Example 9, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) (338 mg) was reacted with phenylacetyl chloride (796 μl), toprepare (S)-methyl2-(2-phenylacetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-12) (210 mg). Yield: 46%, ee=93.5% (chiral HPLC analysis conditionswere the same as those in Example 4), [α]²⁰=+14.00° (c 0.50, MeOH);¹H-NMR (300 MHz, CDCl₃) δ 2.75-2.77 (m, 2H), 2.86-2.88 (m, 2H), 3.52 (d,1H, J=14.3 Hz), 3.63 (d, 1H, J=14.3 Hz), 3.71 (s, 3H), 3.82 (s, 2H),4.89 (s, 1H), 6.26 (s, 1H), 7.23-7.41 (m, 8H), 7.64-7.68 (m, 1H);¹³C-NMR (75 MHz, CDCl₃) δ 24.98, 29.69, 40.87, 48.13, 50.29, 52.13,67.80, 111.90, 125.81, 127.13, 127.45, 128.72, 129.14, 129.26, 129.43,129.80, 129.92, 132.75, 133.70, 134.71, 149.62, 168.30, 171.25; ESI-MSm/z 456.2 [M+H]⁺, 478.2 [M+Na]⁺; HRMS Calcd for C₂₄H₂₃NO₄SCl [M+H]⁺ m/z456.1041, found 456.1036.

Example 17 (S)-Methyl2-(2-(phenoxyacetoxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-13)

Following the method described in Example 9, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7α-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) (169 mg) was reacted with phenoxyacetyl chloride (456 mg), toprepare (S)-methyl2-(2-(phenoxyacetoxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-13) (85 mg). Yield: 36%, mp: 104-106° C., ee=89% (chiral HPLCanalysis conditions were the same as those in Example 4), [α]_(D)²⁰=+32.00° (c 0.50, MeOH); ¹H-NMR (300 MHz, CDCl₃) δ 2.77-2.78 (m, 2H),2.86-2.90 (m, 2H), 3.53 (d, 1H, J=14.3 Hz), 3.65 (d, 1H, J=14.3 Hz),3.71 (s, 3H), 4.82 (s, 2H), 4.90 (s, 1H), 6.32 (s, 1H), 6.92-6.95 (m,2H), 6.99-7.04 (m, 1H), 7.24-7.42 (m, 5H), 7.65-7.68 (m, 1H); ¹³C-NMR(75 MHz, CDCl₃) δ 24.95, 48.07, 50.23, 52.15, 65.14, 67.72, 112.41,114.80, 122.13, 126.14, 127.15, 129.29, 129.48, 129.65, 129.83, 129.93,133.58, 134.73, 148.79, 157.56, 165.88, 171.17; ESI-MS m/z 472.2 [M+H]⁺,494.2 [M+Na]⁺; HRMS Calcd for C₂₄H₂₃NO₅SCl [M+H]⁺ m/z 472.0993, found472.0985.

Example 18 (S)-Methyl2-(2-(ethoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-14)

(2S)-Methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) (85 mg) was dissolved in 10 ml of anhydrous tetrahydrofuran, and0.141 ml of triethylamine was added at room temperature and stirred for10 min. Then, 0.167 ml of ethyl chloroformate was added dropwise at 0°C. After the addition, the reaction solution became a light yellowcloudy solution from a dark red clear solution. The ice bath was removedand the reaction was warmed to 10° C. for 1 hr. Then, 0.07 ml oftriethylamine and 0.1 ml of ethyl chloroformate were additionally addedin an ice bath at 0° C. The ice bath was removed and the reaction waswarmed to 10° C. for 1 hr, at which the raw materials substantiallydisappeared. Water (20 ml) was added, the reaction solution wasextracted with ethyl acetate (30 ml×3) and dried over anhydrous sodiumsulfate, and the solvent was evaporated to give a crude product, whichwas subjected to flash column chromatography (petroleum ether:ethylacetate=40:3) to obtain (S)-methyl2-(2-(ethoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-14) (77 mg). Yield 75%, mp: 42-44° C., ee=97.3% (chiral HPLC analysisconditions were the same as those in Example 4), [α]_(D) ²⁰=+40.00° (c0.50, MeOH); ¹H-NMR (300 MHz, CDCl₃) δ 1.37 (t, 3H, J=7.2 Hz), 2.76-2.78(m, 2H), 2.86-2.90 (m, 2H), 3.52 (d, 1H, J=14.2 Hz), 3.64 (d, 1H, J=14.3Hz), 3.72 (s, 3H), 4.32 (q, 2H, J=7.1, 14.3 Hz), 4.90 (s, 1H), 6.30 (s,1H), 7.24-7.68 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 14.4, 25.4, 48.4,50.5, 52.4, 65.7, 68.1, 112.7, 126.2, 127.4, 129.7, 129.8, 130.1, 130.2,134.0, 135.0, 152.9, 157.3, 171.5; ESI-MS m/z 410.1 [M+H]⁺, 432.1[M+Na]⁺; HRMS Calcd for C₁₉H₂₁NO₅SCl [M+H]⁺ m/z 410.0836, found410.0829.

Example 19 (S)-Methyl2-(2-(isobutoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-15)

Following the method described in Example 18, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7α-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) (85 mg) was reacted with isobutyl chloroformate (0.229 ml), toprepare (S)-methyl2-(2-(isobutoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-15) (75 mg). Yield 69%, ee=95.5% (chiral HPLC analysis conditionswere the same as those in Example 4), [α]_(D) ²⁰=+16.00° (c 0.50, MeOH);¹H-NMR (300 MHz, CDCl₃) δ 0.98 (d, 6H, J=6.7 Hz), 2.01-2.05 (m, 1H),2.76-2.78 (m, 2H), 2.86-2.90 (m, 2H), 3.52 (d, 1H, J=14.3 Hz), 3.64 (d,1H, J=14.4 Hz), 3.72 (s, 3H), 4.25 (d, 2H, J=6.6 Hz), 4.90 (s, 1H), 6.29(s, 1H), 7.26-7.42 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 19.1, 25.4, 28.0,48.4, 50.5, 52.4, 68.1, 75.6, 112.6, 126.1, 127.4, 129.7, 129.8, 130.1,130.2, 134.0, 135.0, 150.8, 153.0, 171.5; ESI-MS m/z 460.3 [M+Na]⁺; HRMSCalcd for C₂₁H₂₅NO₅SCl [M+H]⁺ m/z 438.1150, found 438.1142.

Example 20 (S)-Methyl2-(2-(isopropoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-16)

Following the method described in Example 18, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate (IV-1) (85 mg)was reacted with isopropyl chloroformate (0.23 ml), to prepare(S)-methyl2-(2-(isobutoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-15) (100 mg). Yield: 94%, ee=97.5% (chiral HPLC analysis conditionswere the same as those in Example 4), [α]_(D) ²⁰=+34.00° (c 0.50, MeOH);¹H-NMR (300 MHz, CDCl₃) δ 1.36 (d, 6H, J=6.2 Hz), 2.77-2.78 (m, 2H),2.86-2.89 (m, 2H), 3.52 (d, 1H, J=14.2 Hz), 3.64 (d, 1H, J=14.3 Hz),3.72 (s, 3H), 4.90 (s, 1H), 4.93-5.01 (m, 1H), 6.30 (s, 1H), 7.24-7.68(m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 21.6, 25.4, 48.1, 50.3, 52.1, 67.8,73.9, 112.2, 125.7, 127.1, 129.4, 129.8, 129.9, 130.3, 133.7, 134.7,150.5, 152.0, 171.2; ESI-MS m/z 424.1 [M+H]⁺; HRMS Calcd forC₂₀H₂₃NO₅SCl [M+H]⁺ m/z 424.0989, found 424.0985.

Example 21 (S)-Methyl2-(2-(benzyloxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-17)

Following the method described in Example 18, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7α-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) (85 mg) was reacted with benzyl chloroformate (0.25 ml), toprepare (S)-methyl2-(2-(benzyloxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-17) (97 mg). Yield 82%, ee=93.7% (chiral HPLC analysis conditionswere the same as those in example 4), [α]_(D) ²⁰=+12.00° (c 0.50,CHCl₃); ¹H-NMR (300 MHz, CDCl₃) δ 2.76-2.78 (m, 2H), 2.86-2.90 (m, 2H),3.52 (d, 1H, J=14.4 Hz), 3.63 (d, 1H, J=14.4 Hz), 3.72 (s, 3H), 4.90 (s,1H), 5.26 (s, 2H), 6.30 (s, 1H), 7.24-7.42 (m, 4H); ¹³C-NMR (75 MHz,CDCl₃) δ 25.1, 48.1, 50.3, 52.1, 67.8, 70.9, 112.5, 126.0, 127.0, 127.1,128.6, 128.7, 128.9, 129.4, 129.5, 129.8, 129.9, 133.7, 134.3, 134.7,150.4, 152.6, 171.2; ESI-MS m/z 472.1 [M+H]⁺, 494.1 [M+Na]⁺; HRMS Calcdfor C₂₄H₂₃NO₅SCl [M+H]⁺ m/z 472.0996, found 472.0985.

Example 22 (S)-Methyl2-(2-(N,N-dimethylcarbamoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-18)

In an ice bath, sodium hydride (20 mg, 60%) were added to 6 ml ofanhydrous N, N-dimethyl formamide, to which 169 mg of (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridine-5(2H,4H,6H)-yl)-acetate(IV-1) was then added. The reaction was naturally warmed to roomtemperature, stirred for 1 hr, and then cooled to 0° C. 200 μl ofN,N-dimethylcarbamoyl chloride was slowly added dropwise. The reactionwas naturally warmed to room temperature, and stirred for 3 hrs, and atthis time, TLC showed that the raw materials substantially disappeared.The reaction solution was poured into water (30 ml), the aqueous phasewas extracted with ethyl acetate (50 ml×3), and the organic phase wasdried to obtain a crude product, which was subjected to flash columnchromatography (petroleum ether:ethyl acetate=40:3), to obtain(S)-methyl2-(2-(N,N-dimethylcarbamoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-18) (95 mg). Yield: 45%, mp 96-98° C., ee=93.5% (chiral HPLC analysisconditions were the same as those in Example 10), [α]_(D) ²⁰=+34° (c0.50, MeOH); ¹H-NMR (500 MHz, CDCl₃) δ 2.73-2.76 (m, 2H), 2.85-2.89 (m,2H), 2.99 (s, 3H), 3.03 (s, 3H), 3.52 (d, 1H, J=14.3 Hz), 3.63 (d, 1H,J=14.3 Hz), 3.72 (s, 3H), 4.91 (s, 1H), 6.19 (s, 1H), 7.26-7.69 (m, 4H);¹³C-NMR (75 MHz, CDCl₃) δ 25.03, 36.37, 36.88, 48.18, 50.40, 52.12,67.87, 111.48, 125.38, 127.12, 129.09, 129.37, 129.76, 129.95, 130.56,133.80, 134.34, 134.68, 151.04, 171.27; ESI-MS m/z 409.2 [M+H]⁺; HRMSCalcd for C₁₉H₂₂N₂O₄SCl [M+H]⁺ m/z 409.0992, found 409.0989.

Example 23 (S)-Methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate(I-19)

Following the method described in Example 4, (2S)-methyl2-(2-fluorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-2) (100 mg) was reacted with acetic anhydride (63 μl), to prepare(S)-methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate(I-19) (98.0 mg). Yield 86%. ¹H-NMR (300 MHz, CDCl₃) δ 2.26 (s, 3H),2.47-2.97 (m, 4H), 3.64 (s, 2H), 3.74 (s, 3H), 4.80 (s, 1H), 6.27 (s,1H), 7.07-7.59 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 20.7, 24.9, 48.0,50.0, 52.2, 64.3, 111.9, 115.5, 115.8, 124.4, 124.5, 125.6, 129.0,130.0, 130.1, 130.2, 130.3, 149.6, 159.3, 162.6, 167.7, 171.0; ESI-MSm/z 364.1 [M+H]⁺; HRMS Calcd for C₁₈H₁₉NO₄SF [M+H]⁺ m/z 364.1019, found364.1029.

Example 24 (S)-Methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(4-chlorophenyl)-acetate(I-20)

Following the method described in Example 4, (2S)-methyl2-(4-chlorophenyl)-2-(2-oxo-7,7α-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-3) (100 mg) was reacted with acetic anhydride (63 μl), to prepare(S)-methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(4-chlorophenyl-acetate(I-20) (110 mg). Yield 97%. ¹H-NMR (300 MHz, CDCl₃) δ 2.27 (s, 3H),2.65-2.78 (m, 4H), 3.53 (s, 2H), 3.73 (s, 3H), 4.30 (s, 1H), 6.25 (s,1H), 7.33-7.46 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 20.7, 24.7, 48.1,50.4, 52.2, 71.9, 111.9, 125.7, 128.9, 130.1, 134.3, 134.4, 149.6,167.7, 171.4; ESI-MS m/z 380.1 [M+H]⁺; HRMS Calcd for C₁₈H₁₉NO₄SCl[M+H]⁺ m/z 380.0723, found 380.0735.

Example 25 (S)-Methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-phenyl-acetate(I-21)

Following the method described in Example 4, (2S)-methyl2-phenyl-2-(2-oxo-7,7α-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-4) (100 mg) was reacted with acetic anhydride (63 μl), to prepare(S)-methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-phenyl-acetate(I-21) (108 mg). Yield 93%. ¹H-NMR (300 MHz, CDCl₃) δ 2.26 (s, 3H),2.47-2.91 (m, 4H), 3.54 (s, 2H), 3.72 (s, 3H), 4.32 (s, 1H), 6.25 (s,1H), 7.25-7.69 (m, 5H); ¹³C-NMR (75 MHz, CDCl₃) δ 20.7, 24.4, 48.1,50.3, 52.2, 72.5, 111.9, 128.7, 128.9, 167.7; ESI-MS m/z 346.1 [M+H]⁺;HRMS Calcd for C₁₈H₂₀NO₄S [M+H]⁺ m/z 346.1113, found 346.1125.

Example 26 (S)-Methyl2-(2-(pyrrolidine-1-carbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-22)

Following the method described in Example 22, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7α-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) (84 mg) was reacted with pyrrolidine-1-carbonyl chloride (70 μl),to prepare (S)-methyl2-(2-(pyrrolidine-1-carbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-22) (50 mg). Yield: 46%, ee=80.1% (chiral HPLC analysis conditions:Chiralpak IC 4.6 mm×250 mm; column temperature: 25° C.; mobile phase:50% n-hexane/50% isopropanol/0.1% diethylamine; flow rate: 0.5 ml/min;detection wavelength: UV 254 rnn), [α]_(D) ²²=+19.0° (c 1.0, MeOH);¹H-NMR (300 MHz, CDCl₃) δ 1.87-2.04 (m, 4H), 2.62-2.75 (m, 2H),2.77-2.89 (m, 2H), 3.44-3.54 (m, 5H), 3.61-3.76 (m, 4H), 4.89 (s, 1H),6.20 (s, 1H), 7.22-7.40 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 24.9, 25.1,25.7, 29.7, 46.3, 46.6, 48.2, 50.4, 52.1, 67.9, 111.5, 125.2, 127.1,128.6, 129.1, 129.3, 129.7, 130.0, 133.9, 134.7, 151.0, 151.8, 171.3;ESI-MS m/z 435.1 [M+H]⁺; HRMS Calcd for C₂IH₂₄N₂O₄SCl [M+H]⁺ m/z435.1145, found 435.1148.

Example 27 (S)-Methyl2-(2-(methoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-23)

Following the method described in Example 18, (2S)-methyl2-(2-chlorophenyl)-2-(2-oxo-7,7α-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1) (108.5 mg) was reacted with 0.1 ml of methyl chloroformate, toprepare (S)-methyl2-(2-(methoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-23) (86 mg). Yield: 68%, ee=97.0% (chiral HPLC analysis conditionswere the same as those in Example 4), [α]_(D) ²⁰+24.00° (c 0.50, CHCl₃);¹H-NMR (300 MHz, CDCl₃) δ 2.75-2.78 (m, 2H), 2.83-2.90 (m, 2H),3.47-3.68 (m, 2H), 3.72 (s, 3H), 3.90 (s, 3H), 4.90 (s, 1H), 6.29 (s,1H), 7.23-7.68 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ 25.1, 48.1, 50.3,52.1, 55.8, 67.8, 112.6, 126.0, 127.1, 129.4, 129.6, 129.8, 129.9,133.7, 134.7, 150.4, 153.3, 171.2; ESI-MS m/z 396.1 [M+H]⁺. HRMS Calcdfor C₁₈H₁₉NO₅SCl [M+H]⁺ m/z 396.0672, found 396.0675.

Example 28 (R,S)-Methyl2-(2-(N,N-dimethylcarbamoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-18′)

Following the method described in Example 22, methyl2-(R,S)-2-(2-chlorophenyl)-2-(2-oxo-7,7α-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-5) (169 mg) was reacted with N,N-dimethylcarbamoyl chloride (200μl), to prepare (R,S)-methyl2-(2-(N,N-dimethylcarbamoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-18′) (185 mg). Yield: 87%. ¹H-NMR (300 MHz, CDCl₃) δ 2.73-2.76 (m,2H), 2.85-2.90 (m, 2H), 2.98 (s, 3H), 3.02 (s, 3H), 3.52 (d, 1H, J=14.3Hz), 3.62 (d, 1H, J=14.3 Hz), 3.72 (s, 3H), 4.91 (s, 1H), 6.19 (s, 1H),7.26-7.69 (m, 4H); ESI-MS m/z 409 [M+H]⁺.

Example 29 (R,S)-Methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-2″)

Following the method described in Example 4, methyl2-(R,S)-2-(2-chlorophenyl-7,7α-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate(IV-1″) (650 mg) was reacted with acetic anhydride (1 ml), to prepare(R,S)-methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-2″) (670 mg). Yield 92%. ¹H-NMR (300 MHz, CDCl₃) δ 2.26 (s, 3H), 2.76(d, 2H, J=5.4 Hz), 2.90 (d, 2H, J=5.0 Hz), 3.55 (d, 1H, J=14.2 Hz), 3.64(d, 1H, J=14.2 Hz), 3.72 (s, 3H), 4.90 (s, 1H), 6.26 (s, 1H), 7.25-7.68(m, 4H); ESI-MS m/z 380.0 [M+H]⁺.

Example 30 (S)-Methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetatehydrochloride (I-2 hydrochloride)

103 mg of (S)-methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-2) was dissolved in 6 ml of diethyl ether, and stirred in an ice-saltbath at −10° C. A hydrogen chloride saturated ethanol solution (0.2 ml)was added slowly dropwise, till the system reached about pH 2, at whicha white solid was precipitated immediately. It was stirred for 5 min,allowed to stand, quickly filtered under a nitrogen atmosphere, andwashed with a suitable amount of diethyl ether. The resulting solid wasdried in vacuum to obtain the I-2 hydrochloride (101 mg, white solid).

Yield: 90%, and melting range: 100-120° C.

Example 31 (S)-methyl2-(2-pivaloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetatehydrochloride (I-7 hydrochloride)

65 mg of (S)-methyl2-(2-pivaloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-7) was dissolved in 4 ml of diethyl ether, and stirred in an ice-saltbath at −10° C. A hydrogen chloride saturated ethanol solution (0.2 ml)was added slowly dropwise, till the system reached about pH 2, at whicha white solid was precipitated immediately. It was stirred for 5 min,allowed to stand, quickly filtered under a nitrogen atmosphere, andwashed with a suitable amount of diethyl ether. The resulting solid wasdried in vacuum to obtain the I-7 hydrochloride (65 mg, granular solid).Yield: 92%, melting point: 135-137° C.; ¹H-NMR (300 MHz, CDCl₃) δ 1.33(s, 9H), 3.08 (s, 2H), 3.44-3.51 (m, 2H), 3.82 (s, 4H), 4.34 (s, 1H),5.59 (s, 1H), 6.39 (s, 1H), 7.44-7.50 (m, 3H), 8.36 (d, 1H, J=7.2 Hz).

Example 32 (S)-methyl2-(2-(2,2-dimethylbutanoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetatehydrochloride (I-8 hydrochloride)

63 mg of (S)-methyl2-(2-(2,2-dimethylbutanoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate(I-8) was dissolved in 4 ml of diethyl ether, and stirred in an ice-saltbath at −10° C. A hydrogen chloride saturated ethanol solution (0.2 ml)was added slowly dropwise, till the system reached about pH 2, at whicha white solid was precipitated immediately. It was stirred for 5 min,then allowed to stand, quickly filtered under a nitrogen atmosphere, andwashed with a suitable amount of diethyl ether. The resulting solid wasdried in vacuum to obtain the I-8 hydrochloride (60 mg, white granularsolid). Yield: 88%, melting point: 133-135° C.; ¹H-NMR (300 MHz, CDCl₃)δ 0.91 (t, 3H, J=7.6 Hz), 1.29 (s, 6H), 1.69 (q, 2H, J=7.4 Hz), 3.08 (s,1H), 3.48 (m, 2H), 3.83 (s, 4H), 4.35 (s, 1H), 5.59 (s, 1H), 6.37 (s,1H), 7.44-7.50 (m, 3H), 8.36 (d, 1H, J=6.84 Hz).

Example 33

Anti-Platelet Aggregation Activity Test

Agents and preparations: clopidogrel sulfate was used as a positivecontrol. The positive control and the test compounds (prepared in theabove examples) were formulated in 0.5% CMC-Na (carboxymethylcellulosesodium) into suspensions for administration to animals.

Animals: male SD rats, weighed about 250 g, and supplied by ShanghaiSuper-B&K Laboratory Animal Corp. Ltd. Animal certificate No.:2008001605451, and license No.: SCXK (Hu); SCXK (Hu) 2008-0016.

Instruments: a centrifuge (80-2 bench top low-speed centrifuge), anautomatic platelet aggregation tester (STELLEXLG-PAPER-I plateletcoagulation/aggregation analyzer), and others.

Methods: the pharmacological activity test of the compounds of thepresent invention for platelet aggregation was performed followingBorn's turbidimetric method (Nature, 1962, 194(4832): 927). Anagglomeration-promoting substance, adenosine diphosphate (ADP), wasadded to a platelet rich plasma (PRP), and stirred to allow platelets toaggregate. The aggregation of platelets resulted in the change ofoptical density, which could be detected by a spectrometer. Thisexperiment can be used to evaluate the platelet aggregation effectinduced by the test compounds administrated in-vivo or in-vitro.

Anti-platelet aggregation activity test: the male SD rates weighed about250 g were given with clopidogrel sulfate and the test agents(homogeneous suspensions in 0.5% CMC-Na at a concentration of 1 mg/ml)by oral gavage at a dose of 10 mg/kg or 3 mg/kg, and the blank controlwas given with the same volume of 0.5% CMC-Na by oral gavage. After 2hrs, blood samples were collected from eye sockets of the rats using3.8% sodium citrate as anticoagulant at a ratio of whole blood toanticoagulant of 9:1, and centrifuged at 1000 rpm for 7 min to prepare aplatelet rich plasma (PRP). The PRP was adjusted with a platelet poorplasma (PPP) to maintain the platelet counts at 2×10⁶/ml. The PRP wastaken into a test cup, and incubated at 37° C. for 10 min. Lighttransmission was adjusted to 0% with PRP and to 100% with PPP for eachmeasurement. By using ADP (with a final concentration of 5 μM) as aninducer, the platelet aggregation percentages were measured through theturbidimetric method using a platelet aggregation tester, andstatistically compared by t-test. The platelet aggregation inhibitionwas calculated by the equation:

platelet aggregation inhibition (%)=[1−(aggregation percent in dosedtube/aggregation percent in control tube)]×100%.

Results: the platelet aggregation inhibition after oral administrationof the test compounds to the rats is determined through theturbidimetric method, and some test results are shown in Table 1. Theresults show that most of the test compounds exhibit a more potentanti-platelet aggregation activity than clopidogrel, and the compoundsof (S)-configuration (e.g. I-2′, Example 5) exhibit a more potentplatelet aggregation inhibition than the corresponding enantiomers of(R)-configuration (e.g. I-2′, Example 6) and racemic mixtures (e.g.I-2″, Example 29).

TABLE 1 Platelet aggregation inhibition after oral administration oftest compounds to rats Aggregation Dosage Animals inhibition Testcompounds (mg/kg) (n) (%) Blank control — 6 — Clopidogrel sulfate 10 679.6 3 6 15.4 I-1 (Example 4) 3 6 41.1 I-2 (Example 5) 10 6 83.5 3 669.9 I-2′ (Example 6) 10 6 55.3 3 6 27.1 I-2″ (Example 29) 10 6 78.5 3 643.92 I-3 (Example 7) 3 6 38.4 I-4 (Example 8) 3 6 46.2 I-5 (Example 9)3 6 55.1 I-6 (Example 10) 3 6 31.3 I-7 (Example 11) 3 6 41.9 I-8(Example 12) 3 6 35.7 I-9 (Example 13) 3 6 30.3 I-10 (Example 14) 3 636.8 I-11 (Example 15) 3 6 13.6 I-12 (Example 16) 3 6 18.3 I-13 (Example17) 3 6 10.1 I-14 (Example 18) 3 6 62.9 I-15 (Example 19) 3 6 45.3 I-16(Example 20) 3 6 52.7 I-18 (Example 22) 3 6 48.2 I-19 (Example 23) 3 663.5 I-20 (Example 24) 3 6 17.6 I-21 (Example 25) 3 6 9.1 I-22 (Example26) 3 6 20.3 I-18′ (Example 28) 3 6 29.8

Example 34

Researches on Pharmacokinetics and Bioavailability of Compound I-2 inRats

Research background: it is reported (Thromb Haemost, 2000, 84: 891; DrugMetab Rev 2005, 37 (Suppl 2): 99) that oxidative metabolism ofclopidogrel in vivo by the liver P450 enzyme system first produces themetabolic intermediate (2S)-methyl2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-2-(2-chlorophenyl)-acetate(thiolactone IV-1, see Example 3 for preparation thereof), and thenCompound IV-1 is further rapidly metabolized into the pharmacologicallyactive metabolite. Therefore, Compound IV-1 is useful as an indicatorfor the production of the active metabolite of clopidogrel (Drug MetabDisp 2002, 30: 1288).

Experimental purposes: (1) the plasma concentration-time curves ofCompound I-2, clopidogrel, and metabolite IV-1 thereof after the ratsare respectively given with Compound I-2 and clopidogrel by oral gavageare investigated, so as to estimate corresponding pharmacokineticparameters, evaluate the pharmacokinetic characteristics of Compound I-2and clopidogrel in rats, determine the conversion of Compound I-2 intothe metabolite IV-1 and the conversion degree, and compare therespective conversion degrees of Compound I-2 and clopidogrel to themetabolite IV-1; and (2) the plasma concentration-time curves ofCompound IV-1 after administration to the rats via intravenous injectionare investigated, so as to estimate corresponding pharmacokineticparameters, and evaluate the absolute bioavailability of the metaboliteIV-1 produced through respective metabolism of Compound I-2 andclopidogrel in the rats.

Methods: male SD rats weighed 210-230 g were divided into 3 groups atrandom, Compound I-2 group, clopidogrel sulfate group, and Compound IV-1group. The rats were fasted overnight, but allowed free access to water.After 10 h, (1) the Compound I-2 group was administrated with CompoundI-2 by oral gavage in a volume of 8 ml/kg at a concentration of 1.14mg/ml at a dose of 24 μmol/kg, and blood samples were collected fromretro-orbital plexus in rats before dosing (0 h) and at 0.25, 0.5, 1, 2,4, 6, 8, and 24 hrs post-dose; (2) the clopidogrel sulfate group wasadministrated with clopidogrel sulfate by oral gavage in a volume of 8ml/kg at a concentration of 1.26 mg/ml at a dose of 24 μmol/kg, andblood samples were collected from retro-orbital plexus in rats beforedosing (0 h) and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hrs post-dose; and(3) the Compound IV-1 group was administrated with Compound IV-1 viaintravenous injection in a volume of 5 ml/kg at a concentration of 0.54mg/ml at a dose of 8 μmol/kg, and blood samples were collected fromretro-orbital plexus in rats before dosing (0 h) and at 0.083, 0.167,0.5, 1, 2, 4, 6, 8, and 24 hrs post-dose. Plasmas were isolated aftertreatment with an anticoagulant and a stabilizer, the plasma sampleswere processed, and the concentrations of Compound I-2, clopidogrel, andCompound IV-1 in plasmas were measured by LC-MS/MS. Chromatography andMS conditions are shown in Tables 2 and 3.

TABLE 2 Chromatography conditions for samples and internal standard(diazepam) Chromatography ACE 3.0*50 mm, 5 μm, C18, P/NO: ACE-121-0503column Phase A: Phase B: mobile Time water + 0.1% acetonitrile + 0.1%phase (min) formic acid formic acid   0-0.5 75% 25% 0.5-1.5 75%→5%25%→95% 1.5-3.0  5% 95% 3.0-3.2  5%→75% 95%→25% 3.2-4.0 75% 25% Flowrate 0.5 ml/min Injector 10° C. Column 35° C. Injection Total valve timePosition 2.0 B 3.2 A Retention Compound I-2: 2.66 min; Clopidogrel: time2.70 min; Compound IV-1: 2.60 min; (min) and diazepam: 2.50 min

TABLE 3 MS conditions for samples and internal standard (diazepam)Compound Sample IV-1 Clopidogrel Compound Diazepam Ion source ESIPolarity Positive Scan mode Q1, Q3, MRM Nebulizer 40 psi gas Heater gas40 psi Curtain gas 20 psi Spray voltage 5000 V    Declustering 56 V  53V  60 v  105 v Collision gas 36 ev  23 ev 23 ev  42 ev Temperature 500Ion pair m/z 338.2/154.9 322.0/212.0 380.0/212.0 285.3/154.0

Results: the plasma concentration-time data after administration of thetest agents to the SD rats are shown in Tables 4, 5, and 6 (note: NA isnot available). The results show that (1) after 3 SD rats are dosed with24 μmol/kg Compound I-2 by oral gavage, the Compound IV-1 generated bymetabolism has a elimination half-life of t_(1/2)=2.19±1.68 h, an areaAUC_(0-t) under the plasma concentration-time curve of 197±124 μg·h/L,an area AUC_(0-∞), under the plasma concentration-time curve of 211±119μg·h/L, a peak time of T_(max)=1.17±0.764 h, a peak concentration ofC_(max)=67.2±42.3 μg/L, and an absolute bioavailability of 24.6%; (2)after 3 SD rats are dosed with 24 μmol/kg clopidogrel sulfate by oralgavage, the Compound IV-1 generated by metabolism has an eliminationhalf-life of =2.48±0.466 h, an area AUC_(0-t) under the plasmaconcentration-time curve of 29.0±11.5 μg·h/L, an area AUC_(0-∞), underthe plasma concentration-time curve of 32.2±10.9 μg·h/L, a peak time ofT_(max)=0.583±0.382 h, a peak concentration of C_(max)=6.93±3.36 μg/L,and an absolute bioavailability of 3.63%; and (3) after 3 SD rats aredosed with 8 μmol/kg Compound IV-1 via intravenous injection, theCompound IV-1 has an elimination half-life of t_(1/2)=1.06±0.364 h, anarea AUC_(0-t) under the plasma concentration-time curve of 266±37.6μg·h/L, an area AUC_(0-∞), under the plasma concentration-time curve of268±38.3 μg·h/L, a peak time of T_(max)=0.0830 h, and a peakconcentration of C_(max)=671±128 μg/L.

TABLE 4 Concentration-time data (ng/ml) of Compound IV-1 in plasma afteradministration of Compound I-2 to SD rats by oral gavage Animal Time (h)No. 0 0.25 0.5 1 2 4 6 8 24  1# 0 35.5 53.0 65.4 115 32.4 8.59 5.74 ND10# NA 19.4 29.2 34.7 19.6 11.8 4.25 1.56 ND 11# NA 22.5 51.9 37.7 16.612.6 18.9 6.12 ND Mean ± — 25.8 44.7 45.9 50.4 18.9 10.6 4.47 — SD —8.54 13.4 16.9 56.0 11.7 7.53 2.53 —

TABLE 5 Concentration-time data (ng/ml) of Compound IV-1 in plasma afteradministration of clopidogrel sulfate to SD rats by oral gavage AnimalTime (h) No. 0 0.25 0.5 1 2 4 6 8 24  5# 0 8.99 10.3 10.8 7.57 4.70 3.150.895 ND 12# NA 4.73 4.46 4.38 4.27 2.48 1.35 0.887 ND 13# NA 4.18 5.275.09 3.21 2.69 2.87 0.924 ND Mean ± — 5.97 6.68 6.76 5.02 3.29 2.460.902 — SD — 2.63 3.16 3.52 2.27 1.23 0.969 0.0195 —

TABLE 6 Concentration-time data (ng/ml) of Compound IV-1 in plasma afterintravenous injection of Compound IV-1 to SD rats Animal Time (h) No. 00.083 0.167 0.5 1 2 4 6 8 24 7# 0 696 317 108 51.0 10.9 3.94 1.29 ND ND8# 0 785 417 129 49.3 9.06 2.87 0.977 ND ND 9# 0 533 311 107 37.3 9.742.02 1.06 ND ND Mean ± 0 671 348 115 45.9 9.90 2.94 1.11 — — SD 0 12859.5 12.4 7.47 0.930 0.962 0.162 — —

The estimated pharmacokinetic parameters after the SD rats are dosedwith the test agents are shown in Tables 7, 8, and 9. (Note: in Tables7, 8, and 9, it is assumed that Compound I-2 or clopidogrel can betotally converted into Compound IV-1 in the calculation of clearanceCL_(tot) and apparent volume of distribution V, of Compound IV-1, andthus the dosage in the calculation formula is that of Compound I-2 orclopidogrel equivalent to Compound IV-1)

TABLE 7 Pharmacokinetic parameters of metabolite (Compound IV-1) afteradministration of Compound I-2 to SD rats by oral gavage Equivalent ofC_(max) T_(max) t_(1/2) CL_(tot) V₂ AUC_(0-t) AUC_(0-∞) 8.1 mg/kg (μg/L)(h) (h) (L/h/kg) (L/kg) (μg · h/L) (μg · h/L)  1# 115 2.00 1.07 23.736.6 338 342 10# 34.7 1.00 1.37 75.0 148 105 108 11# 51.9 0.500 4.1244.0 261 147 184 Mean ± 67.2 1.17 2.19 47.6 149 197 211 SD 42.3 0.7641.68 25.8 112 124 119

TABLE 8 Pharmacokinetic parameters of metabolite (Compound IV-1) afteradministration of clopidogrel sulfate to SD rats by oral gavageEquivalent of C_(max) T_(max) t_(1/2) CL_(tot) V₂ AUC_(0-t) AUC_(0-∞)8.1 mg/kg (μg/L) (h) (h) (L/h/kg) (L/kg) (μg · h/L) (μg · h/L)  5# 10.81.00 1.95 181 510 42.2 44.7 12# 4.73 0.250 2.65 331 1267 21.1 24.5 13#5.27 0.500 2.83 294 1199 23.7 27.6 Mean ± 6.93 0.583 2.48 269 992 29.032.2 SD 3.36 0.382 0.466 77.9 419 11.5 10.9

TABLE 9 Pharmacokinetic parameters of Compound IV-1 after intravenousinjection of Compound IV-1 to SD rats Compound C_(max) T_(max) t_(1/2)CL_(tot) V₂ AUC_(0-t) AUC_(0-∞) 2.7 mg/kg (μg/L) (h) (h) (L/h/kg (L/kg)(μg · h/L (μg · h/L 7# 696 0.0830 1.30 10.0 18.8 266 269 8# 785 0.08301.25 8.84 15.9 304 306 9# 533 0.0830 0.643 11.8 10.9 229 229 Mean ± 6710.0830 1.06 10.2 15.2 266 268 SD 128 0 0.364 1.49 3.98 37.6 38.3

Conclusions: (1) after being dosed to the rats by oral gavage, CompoundI-2 can be converted into the main intermediate metabolite (CompoundIV-1) of clopidogrel; and (2) by oral gavage, the degree of conversionof Compound I-2 into the metabolite IV-1 is more than 5 times higherthan that of clopidogrel sulfate, and the absolute bioavailability ofthe metabolite IV-1 produced by metabolism of Compound I-2 is also morethan 5 times higher than that of the metabolite IV-1 produced bymetabolism of clopidogrel sulfate.

The above research results suggest that the bioavailability of theintermediate metabolite of Compound I-2 is significantly higher thanthat of clopidogrel, such that the production of the active metabolitethereof is also significantly higher than that of clopidogrel, and thusit is expected that the risk of side effects such as bleeding of theanti-platelet aggregation agent can be reduced while rapid onset ofaction and high efficacy are achieved, by significantly lowering thedosage of the agent.

Example 35

Tablet

Compound I-2 (50 g) prepared in Example 5, hydroxypropyl methylcelluloseE (150 g), starch (200 g), a suitable amount of Povidone K30, andmagnesium stearate (1 g) were mixed, granulated, and tableted.

1-5. (canceled)
 6. A method for preparing an optically active2-hydroxytetrahydrothienopyridine derivative, wherein said derivative is(S)-methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetateor a pharmaceutically acceptable salt thereof,

comprising the following steps: (1) reacting a compound of Formula II

with a compound of Formula III

or a salt thereof in the presence of a base, to obtain a compound ofFormula IV

or a salt thereof, wherein R⁷ is a C₁₋₆ alkyl, trifluoromethyl,pentafluoroethyl, heptafluoropropyl, phenyl, or a Z-substituted phenyl,in which Z is a C₁₋₃ alkyl, halo, cyano, nitro, or trifluoromethyl, andis at position 2, 3 or 4 of the phenyl ring; and (2) reacting thecompound of Formula IV or the salt thereof with a compound of Formula V

or a compound of Formula VI

in the presence of a base, to obtain the compound of Formula I,

7-8. (canceled)
 9. A method for preparing an optically active2-hydroxytetrahydrothienopyridine derivative, wherein said derivative is(S)-methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetateor a pharmaceutically acceptable salt thereof, comprising the followingsteps: reacting a compound of Formula II

with a compound of Formula VII

or a salt thereof in the presence of a base, to obtain the compound ofFormula I,

wherein R⁷ is a C₁₋₆ alkyl, trifluoromethyl, pentafluoroethyl,heptafluoropropyl, phenyl, ora Z-substituted phenyl, in which Z isalkyl, halo, cyano, nitro, or trifluoromethyl, and is at position 2, 3or 4 of the phenyl ring. 10-16. (canceled)
 17. The method according toclaim 6, wherein in the step (1), a reaction solvent is used and is oneor more selected from benzene, toluene, chloroform, n-hexane,cyclohexane, dichloromethane, 1,2-dichloroethane, methyl t-butyl ether,carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate,methanol, ethanol, acetone, tetrahydrofuran, diethyl ether,acetonitrile, N,N-dimethyl formamide, or dimethyl sulfoxide; the baseused is selected from triethylamine, diisopropyl ethylamine,1,8-diazabicyclo[5,4,0]undec-7-ene, potassium carbonate, sodiumcarbonate, potassium bicarbonate, or sodium bicarbonate; the reactiontemperature is from −20° C. to 100° C.; and the salt of the compound ofFormula III is selected from hydrochloride, p-toluenesulfonate, acetate,sulfate, phosphate, trifluoromethane sulfonate, oxalate,methanesulfonate, benzenesulfonate, or hydrobromide; and wherein in thestep (2), a reaction solvent is used and is one or more selected frombenzene, toluene, chloroform, n-hexane, cyclohexane, dichloromethane,1,2-dichloroethane, methyl t-butyl ether, carbon tetrachloride, ethylacetate, propyl acetate, butyl acetate, methanol, ethanol, acetone,tetrahydrofuran, diethyl ether, acetonitrile, N,N-dimethyl formamide, ordimethyl sulfoxide; the base used is selected from triethylamine, sodiumhydride, potassium hydride, 1,8-diazabicyclo[5,4,0]undec-7-ene,pyridine, diisopropylethylamine, lithium diisopropylamide, potassiumcarbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate,potassium t-butoxide, or sodium t-butoxide; and the reaction temperatureis from −20° C. to 100° C.
 18. The method according to claim 17, whereinin the step (1), said reaction solvent is one or more selected fromN,N-dimethyl formamide, tetrahydrofuran, acetonitrile, ordichloromethane; and said reaction temperature is from 10° C. to 60° C.19. The method according to claim 17, wherein in the step (2), saidreaction solvent is one or more selected from tetrahydrofuran,acetonitrile, or N,N-dimethyl formamide; and said reaction temperatureis from 0° C. to 50° C.
 20. The method according to claim 9, wherein areaction solvent is used and is one or more selected from benzene,toluene, chloroform, n-hexane, cyclohexane, dichloromethane,1,2-dichloroethane, methyl t-butyl ether, carbon tetrachloride, ethylacetate, propyl acetate, butyl acetate, methanol, ethanol, acetone,tetrahydrofuran, diethyl ether, acetonitrile, N,N-dimethyl formamide, ordimethyl sulfoxide; the base used is selected from triethylamine,diisopropyl ethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, potassiumcarbonate, sodium carbonate, potassium bicarbonate, or sodiumbicarbonate; the reaction temperature is from −20° C. to 100° C.; andthe salt of the compound of Formula VII is selected from hydrochloride,p-toluenesulfonate, acetate, sulfate, phosphate, trifluoromethanesulfonate, oxalate, methanesulfonate, benzenesulfonate, or hydrobromide.21. The method according to claim 20, wherein said solvent is one ormore selected from N,N-dimethyl formamide, tetrahydrofuran,acetonitrile, or dichloromethane; and the reaction temperature is from10° C. to 60° C.
 22. A method for preparing an optically active2-hydroxytetrahydrothienopyridine derivative, wherein said derivative is(S)-methyl2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetateor a pharmaceutically acceptable salt thereof, comprising the followingsteps: reacting the compound of Formula IV

or the salt thereof with a compound of Formula V

or a compound of Formula VI

in the presence of a base, to obtain the compound of Formula I,


23. The method according to claim 22, wherein a reaction solvent is usedand is one or more selected from benzene, toluene, chloroform, n-hexane,cyclohexane, dichloromethane, 1,2-dichloroethane, methyl t-butyl ether,carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate,methanol, ethanol, acetone, tetrahydrofuran, diethyl ether,acetonitrile, N,N-dimethyl formamide, or dimethyl sulfoxide; the baseused is selected from triethylamine, sodium hydride, potassium hydride,1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, diisopropylethylamine,lithium diisopropylamide, potassium carbonate, sodium carbonate,potassium bicarbonate, sodium bicarbonate, potassium t-butoxide, orsodium t-butoxide; and the reaction temperature is from −20° C. to 100°C.